EP0302186A2 - Medical device and method for making it - Google Patents

Medical device and method for making it Download PDF

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Publication number
EP0302186A2
EP0302186A2 EP88107039A EP88107039A EP0302186A2 EP 0302186 A2 EP0302186 A2 EP 0302186A2 EP 88107039 A EP88107039 A EP 88107039A EP 88107039 A EP88107039 A EP 88107039A EP 0302186 A2 EP0302186 A2 EP 0302186A2
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EP
European Patent Office
Prior art keywords
medical device
isocyanate
polyol
metal ion
chain extenders
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EP88107039A
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German (de)
French (fr)
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EP0302186A3 (en
EP0302186B1 (en
Inventor
Otto Brenner
Wolfgang Dr. Ermert
Helmut Dr. Eschwey
Gerd Dr. Esswein
Günter Dr. Schuhmacher
Martin Dr. Thaler
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Carl Freudenberg KG
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Carl Freudenberg KG
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Priority to AT88107039T priority Critical patent/ATE75953T1/en
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Publication of EP0302186A3 publication Critical patent/EP0302186A3/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • the present invention relates to a medical device according to the preamble of claim 1 and a method for its production.
  • microbicidal effect of heavy metal ions such as gold, silver or copper, which is often referred to as oligodynamic in the literature (e.g.: The Journal of Urology, 121 ⁇ January 1979>, 40 ff.), Is used in medical technology for plastic endoprostheses or tubular catheters , such as B. urethral catheter for a long period of time to equip microbicidal.
  • the US-PS 4,054,139 proposes to this end, a tubular catheter on its inner and outer surface with at least one oligodynamic agent, e.g. B. silver or its compounds.
  • at least one oligodynamic agent e.g. B. silver or its compounds.
  • the alternative of manufacturing the matrix for the metal ion-donating substances from polyurethane allows the reversible embedding of these substances down to the innermost material zones, since polyurethane is also sufficiently hydrophilic inside and could therefore release metal ions under the influence of body fluid.
  • devices constructed in this way as measurements have shown, have such low delivery rates for oligodynamically active substances that a sufficient amount of effective ions, measured in terms of the concentration of the germs to be destroyed, is not available for continuous use.
  • thermoplastic polyurethane-silicone elastomer material From EP-PS 0 068 385 the pronounced antithrombogenic effect of a thermoplastic polyurethane-silicone elastomer material and its advantageous use for medical molded parts that are brought into direct contact with blood have become known.
  • Block copolymers of a polyurethane and an organic silicone polymer with fewer silicone than polyurethane units which are known from US Pat. No. 3,562,352, are discussed there with regard to their mechanical and antithrombogenic properties in direct blood contact, and a new, advantageous variant is described in detail: These are: 4 to 15% by weight of an organic silicone polymer with a molecular weight of 500 to 10,000 and plasticizing polyether or polyester segments are introduced into the polymer main chain.
  • This material also contains no medically effective active ingredients to be released; the European patent specification does not contain any indication of its usability for medical devices which have a microbicidal action and are not associated with blood.
  • the invention has for its object to provide a medical device to be used in the living body, tissue penetrating body tissue, which has a significantly increased delivery capacity for microbicidal, metal ion-releasing substances and good tissue tolerance and which the metal ions in a controlled amount over a longer period of time to each of them Is able to give back the outside when it comes into contact with body fluid.
  • tissue penetrating body tissue which has a significantly increased delivery capacity for microbicidal, metal ion-releasing substances and good tissue tolerance and which the metal ions in a controlled amount over a longer period of time to each of them Is able to give back the outside when it comes into contact with body fluid.
  • a method for producing such a medical device is to be demonstrated, with spatially uniform embedding of the metal ion-releasing substance in finely divided form in the polymer matrix being possible even during its production without complicated mechanical or chemical aftertreatment of the material or the finished part.
  • silicon polyurethane The material class known per se proposed according to the invention is hereinafter referred to as "silicone polyurethane".
  • the production and properties of this material are not critical to the present invention and, depending on the desired requirements, can be derived from the prior art without inventive step within the framework of the claimed teaching.
  • metal salts As a metal ion, microbicidal, oligodynamically active substance z.
  • the spatial embedding of the active substances into the silicone-polyurethane matrix according to the invention by 1 to 15 percent increases the usable amount of the ions available compared to the usual coatings by 40% and more.
  • the invention is preferably, but not exclusively, to be used when the devices in question must remain in contact with body tissue not only temporarily, but longer; it includes e.g. B. endoprostheses, catheters, probes, endoscopes, implants and drainage.
  • the polymer matrix made of silicone polyurethane which forms the device according to the invention contains the entire oligodynamic active ingredient, in addition to the advantage of releasing the metal ions to both outer surfaces of the device body, there is also the advantageous effect that at the beginning of the application, where an increased number of Bacteria, microbes and germs can be present, an increased amount of active ingredient is released as soon as all surface areas of the matrix are saturated with body fluid. After a longer period of time, there is a steadily decreasing supply of metal ions, the release of which is now determined by their path length during the migration from the interior of the matrix to its surface.
  • the configuration of the medical device according to the invention thus automatically adjusts the rate of release of metal ions to the amount of organisms to be controlled.
  • the metal ion-releasing substance should expediently not contain any grain sizes larger than 50 ⁇ m, since exceeding this limit can have a negative effect on the mechanical stability of the matrix.
  • a preferred method for producing the device according to the invention is that the polypol, the organic silicone polymer and the isocyanate and, if appropriate, the chain extenders and / or crosslinking substances are allowed to react with one another and then brought into the desired shape.
  • the metal ion-donating substance with a proportion of the total polymer mass of 1 to 15% by weight is admixed as a powder with a grain size ⁇ 50 ⁇ m before the addition of the isocyanate and dewatered together with the polyol.
  • a further, particularly preferred method consists in using a readily water-soluble, metal ion-releasing substance instead of the powder and admixing it as an aqueous solution with a solids content as in the powder addition described above and at the same point as above, and then dewatered and then add the isocyanate.
  • This variant of the method offers the advantage of being able to introduce the active substance into the matrix in the smallest possible form, namely as discrete ions and thus in an optimally uniform manner.
  • a one-step shaping and bactericidal / microbicidal treatment of the medical device is achieved. Any post-treatment is eliminated, which completely eliminates the handling of solvents, the swelling or dissolving of the substrate or problems with the adhesion of coatings.
  • thermoplastic material If you want to obtain a thermoplastic material, the finished polyurethane with active ingredient is granulated, dried and then either injection molded or extruded.
  • thermoset devices e.g. B. probes, the shaping takes place immediately after the reaction of the starting materials by pouring into a molded part.
  • the desired medical device can be manufactured in a continuous process step.
  • the following example describes a manufacturing method for a medical device made of a thermoplastic material in a non-restrictive manner:
  • the finished product is allowed to harden on the hot plate, then granulated and dried in a warm air oven at 110 ° C. for two hours. Finally, the granules are shaped into an urethral catheter on an injection molding machine.
  • the catheter manufactured in this way has the following material properties: Tensile strength (DIN 53 504): 20 MPa Elongation at break (DIN 53 504): 500% Hardness (DIN 53 305): 70 shore A These material data show the mechanical suitability of the thermoplastic material for the production of catheters and implants.

Abstract

A medical device which can be introduced into the body tissue of a human or animal comprises a matrix of a polyurethane elastomer with organic silicone polymer units built into the main polymer chain and an oligodynamic agent spatially distributed uniformly within the matrix. The oligodynamic agent releases bacteriocidal or microbicidal metal ions when exposed to body tissues. The method for manufacturing the medical device is characterized by the addition of the oligodynamic agent in a solid or dissolved form prior to the reaction of the educts with isocyanate.

Description

Die vorliegende Erfindung betrifft ein medizinisches Gerät nach dem Oberbegriff des Anspruchs 1 sowie ein Verfahren zu seiner Herstellung.The present invention relates to a medical device according to the preamble of claim 1 and a method for its production.

Die in der Literatur (z.B.: The Journal of Urology, 121 <Januar 1979>, 40 ff.) häufig als oligodynamisch bezeich­nete Mikrobizidwirkung von schwermetallionen, wie Gold, Sil­ber oder Kupfer, wird in der Medizintechnik genutzt, um Kunststoff-Endoprothesen oder Schlauchförmige Katheter, wie z. B. Harnröhrenkatheter, für eine längere Zeitdauer mikrobizid auszurüsten.The microbicidal effect of heavy metal ions such as gold, silver or copper, which is often referred to as oligodynamic in the literature (e.g.: The Journal of Urology, 121 <January 1979>, 40 ff.), Is used in medical technology for plastic endoprostheses or tubular catheters , such as B. urethral catheter for a long period of time to equip microbicidal.

Die US-PS 4,054,139 schlägt hierzu vor, einen röhrenförmi­gen Katheter auf seiner Innen- und auf seiner Außenfläche mit mindestens einem oligodynamischen Agens, z. B. Silber oder seinen Verbindungen, zu versehen.The US-PS 4,054,139 proposes to this end, a tubular catheter on its inner and outer surface with at least one oligodynamic agent, e.g. B. silver or its compounds.

Um die Oberfläche eines solchen medizinischen Gerätes in quantitativer Hinsicht noch aufnahmefähiger für Metallionen abgebende Substanzen zu machen, wird in der US-PS 4,612,337 gelehrt, das Polymermaterial, z. B. ein Polyurethan oder Silikon-Elastomer, durch zweimaliges Tränken bzw. Quellen mit geeigneten Lösungsmitteln (für das Mikrobizid bzw. für das Metallsalz) zu behandeln und jeweils anschließend, zu­letzt nach dem Auswaschen, zu trocknen.In order to make the surface of such a medical device quantitatively more receptive to metal ion donating substances, it is taught in US Pat. No. 4,612,337 that the polymer material, e.g. B. a polyurethane or silicone elastomer, by twice impregnating or swelling with suitable solvents (for the microbicide or for the metal salt) and then to dry each time, finally after washing.

Unbefriedigend ist bei allen bekannten Lösungen, bei denen eine innen- und außenseitige mikrobizide Ausrüstung des Ge­rätes erwünscht ist, der hohe Arbeitsaufwand des Beschich­tens der Oberflächen.In all known solutions in which an inside and outside microbicidal treatment of the device is desired, the high workload of coating the surfaces is unsatisfactory.

Da ferner die Metallionen abgebenden Substanzen stets nur in den Oberflächenbereichen des Polymerwerkstoffes gebun­den vorliegen, ist ihre Verfügbarkeit zeitlich und mengen­mäßig begrenzt, was bei Langzeitbehandlungen einen häufi­gen, risikoreichen und schmerzhaften Austausch mit neu be­schichteten Geräten erforderlich macht.Furthermore, since the substances that give off metal ions are always bound only in the surface areas of the polymer material, their availability is limited in terms of time and quantity, which means that long-term treatments require frequent, risky and painful exchanges with newly coated devices.

Für alle nicht flächig aufgebauten, sondern eine Raumform­aufweisenden, intracorporal zu verwendenden Geräte, z. B. Katheter oder Prothesen, stößt man bereits bei etwas größe­ren Materialdicken an die Grenzen der Einlagerungs- oder Abgabefähigkeit für Metallionen abgebende Substanzen: Im Falle von Silikon-Elastomeren scheitert man daran, daß die inneren Bereiche dieses Materials wegen ihrer Hydrophobie für Körperflüssigkeit nicht oder nicht in ausreichendem Ma­ße zugänglich sind. Dies bedeutet jedoch nichts anderes, als daß den tiefer in die Matrix eingebetteten Ionen kein Trägermedium mehr zur Verfügung steht, mittels dessen sie wieder nach außen wandern könnten, um ihre mikrobizide Wir­kung in dem den Katheter umgebenden Körpergewebe zu entfal­ten. Es sind somit nach wie vor lediglich die an der Ober­fläche befindlichen Agenzien wirksam.For all devices that are not flat, but have a spatial shape that can be used intracorporeally, e.g. B. catheters or prostheses, one reaches the limits of the storage or dispensing ability for metal ion-releasing substances even with somewhat larger material thicknesses: In the case of silicone elastomers, one fails because the inner areas of this material do not or not because of their hydrophobicity for body fluids are sufficiently accessible. However, this means nothing other than that the carrier medium is no longer available to the ions embedded deeper into the matrix, by means of which they could migrate outward again in order to develop their microbicidal action in the body tissue surrounding the catheter. Only the agents on the surface are still effective.

Die Alternative, die Matrix für die Metallionen abgebenden Substanzen aus Polyurethan zu fertigen, läßt zwar die re­versible Einbettung dieser Substanzen bis in innerste Werk­stoffzonen zu, da Polyurethan ausreichend hydrophil auch in seinem Innern ist und unter Einwirkung von Körperflüssig­keit somit durchaus Metallionen abgeben könnte. Solcherma­ßen aufgebaute Geräte jedoch weisen, wie Messungen ergaben, derart niedrige Abgaberaten für oligodynamisch wirksame Substanzen auf, daß eine, gemessen an der Konzentration der zu vernichtenden Keime, ausreichende Menge an wirksamen Ionen bei Daueranwendung nicht zur Verfügung steht.The alternative of manufacturing the matrix for the metal ion-donating substances from polyurethane allows the reversible embedding of these substances down to the innermost material zones, since polyurethane is also sufficiently hydrophilic inside and could therefore release metal ions under the influence of body fluid. However, devices constructed in this way, as measurements have shown, have such low delivery rates for oligodynamically active substances that a sufficient amount of effective ions, measured in terms of the concentration of the germs to be destroyed, is not available for continuous use.

Aus der EP-PS 0 068 385 ist die ausgeprägt antithrombogene Wirkung eines thermoplastischen Polyurethan-Silikon-Elasto­merwerkstoffes und dessen vorteilhafte Verwendung für medi­zinische Formteile, die unmittelbar mit Blut in Kontakt ge­bracht werden, bekanntgeworden. Es werden dort aus der US-PS 3,562,352 vorbekannte Block-Copolymere aus einem Po­lyurethan und einem organischen Silikonpolymeren mit weni­ger Silikon- als Polyurethan-Einheiten bezüglich ihrer me­chanischen sowie antithrombogenen Eigenschaften bei unmit­telbarem Blutkontakt diskutiert sowie eine neuartige, vor­teilhafte Variante ausführlich beschrieben: Bei dieser sind in die Polymer-Hauptkette 4 bis 15 Gew.-% eines organischen Silikonpolymeren mit einem Molekulargewicht von 500 bis 10.000 und weichmachende Polyether- oder Polyester-Segmente eingebracht. Auch dieser Werkstoff enthält keine medizi­nisch wirksamen, nach außen abzugebenden Wirkstoffe; ein Hinweis auf seine Verwendbarkeit für mikrobizid wirkende, nicht mit Blut in Verbindung stehende medizinische Geräte ist auch in der Europäischen Patentschrift nicht enthalten.From EP-PS 0 068 385 the pronounced antithrombogenic effect of a thermoplastic polyurethane-silicone elastomer material and its advantageous use for medical molded parts that are brought into direct contact with blood have become known. Block copolymers of a polyurethane and an organic silicone polymer with fewer silicone than polyurethane units, which are known from US Pat. No. 3,562,352, are discussed there with regard to their mechanical and antithrombogenic properties in direct blood contact, and a new, advantageous variant is described in detail: These are: 4 to 15% by weight of an organic silicone polymer with a molecular weight of 500 to 10,000 and plasticizing polyether or polyester segments are introduced into the polymer main chain. This material also contains no medically effective active ingredients to be released; the European patent specification does not contain any indication of its usability for medical devices which have a microbicidal action and are not associated with blood.

Der Erfindung liegt die Aufgabe zugrunde, ein im lebenden Körper zu verwendendes, Körpergewebe durchdringendes medi­zinisches Gerät anzugeben, welches eine wesentlich erhöhte Abgabekapazität für mikrobizide, Metallionen abgebende Sub­stanzen und eine gute Gewebeverträglichkeit aufweist und welches die Metallionen in kontrollierter Menge über einen längeren Zeitraum zu jeder seiner Außenseiten wieder abzu­geben imstande ist, wenn es mit Körperflüssigkeit in Berüh­rung kommt. Zugleich soll ein Verfahren zur Herstellung eines solchen medizinischen Gerätes aufgezeigt werden, wo­bei ohne umständliche mechanische oder chemische Nachbe­handlung des Werkstoffes oder des Fertigteils eine räumlich gleichmäßige Einbettung der Metallionen abgebenden Substanz in feinst verteilter Form in die Polymermatrix bereits wäh­rend deren Herstellung möglich ist.The invention has for its object to provide a medical device to be used in the living body, tissue penetrating body tissue, which has a significantly increased delivery capacity for microbicidal, metal ion-releasing substances and good tissue tolerance and which the metal ions in a controlled amount over a longer period of time to each of them Is able to give back the outside when it comes into contact with body fluid. At the same time, a method for producing such a medical device is to be demonstrated, with spatially uniform embedding of the metal ion-releasing substance in finely divided form in the polymer matrix being possible even during its production without complicated mechanical or chemical aftertreatment of the material or the finished part.

Die Lösung dieser Aufgabe besteht, ausgehend von US-PS 4,054,139, in einen gattungsgemäßen medizinischen Gerät mit den kennzeichnenden Merkmalen des Anspruchs 1. Besonders bevorzugte Herstellungsverfahren werden in den Ansprüchen 2 und 3 dargelegt.This problem is solved, starting from US Pat. No. 4,054,139, in a generic medical device with the characterizing features of claim 1. Particularly preferred production methods are set out in claims 2 and 3.

Die erfindungsgemäß vorgeschlagene, an sich bekannte Werk­stoffklasse wird im folgenden "Silikonpolyurethan" genannt. Herstellung und Eigenschaften dieses Werkstoffes sind für die vorliegende Erfindung nicht kritisch und je nach den ge­wünschten Anforderungen ohne erfinderisches Zutun im Rahmen der beanspruchten Lehre aus dem Stand der Technik herleitbar.The material class known per se proposed according to the invention is hereinafter referred to as "silicone polyurethane". The production and properties of this material are not critical to the present invention and, depending on the desired requirements, can be derived from the prior art without inventive step within the framework of the claimed teaching.

Als Metallionen abgebende, mikrobizide, oligodynamisch wirk­same Substanz werden z. B. Metallsalze, deren Oxide und Car­bide sowie metallorganische Verbindungen verstanden, wie sie in der Medizin bezüglich Wirkung und Anwendung wohlbekannt sind.As a metal ion, microbicidal, oligodynamically active substance z. B. metal salts, their oxides and carbides as well as organometallic compounds understood as they are well known in medicine with regard to effect and application.

Die erfindungsgemäß 1- bis15prozentige räumliche Einbettung der aktiven Substanzen in die Silikonpolyurethan-Matrix er­höht die nutzbare Menge der zur Verfügung stehenden Ionen gegenüber den üblichen Beschichtungen um 40% und mehr.The spatial embedding of the active substances into the silicone-polyurethane matrix according to the invention by 1 to 15 percent increases the usable amount of the ions available compared to the usual coatings by 40% and more.

Überraschenderweise wurde gefunden, daß der Kontakt von Kör­perflüssigkeit mit den inneren Bereichen des bisher nur für andere Zwecke als vorteilhaft bekannten Silikonpolyurethan-­Werkstoffes sicher gewährleistet ist, auch wenn die Polymer­matrix für gattungsgemäße Geräte übliche Dicken von bis zu 2 mm aufweist.Surprisingly, it has been found that the contact of body fluid with the inner areas of the silicone polyurethane material, which has hitherto been known only for other purposes as advantageous, is reliably ensured, even if the polymer matrix for devices of the generic type has customary thicknesses of up to 2 mm.

Die Erfindung ist vorzugsweise, jedoch nicht ausschließlich, dann anzuwenden, wenn die betreffenden Geräte nicht nur vorübergehend, sondern länger im Körpergewebekontakt ver­bleiben müssen; sie umfaßt z. B. Endoprothesen, Katheter, Sonden, Endoskope, Implantate und Dränagen.The invention is preferably, but not exclusively, to be used when the devices in question must remain in contact with body tissue not only temporarily, but longer; it includes e.g. B. endoprostheses, catheters, probes, endoscopes, implants and drainage.

Da die das Gerät bildende polymere Matrix aus Silikonpoly­urethan erfindungsgemäß zur Gänze den oligodynamischen Wirkstoff enthält, tritt, neben dem Vorteil der Abgabe der Metallionen zu beiden Außenflächen des Gerätekörpers hin, noch der vorteilhafte Effekt auf, daß zu Beginn der Anwen­dung, wo eine erhöhte Zahl von Bakterien, Mikroben und Kei­men anwesend sein kann, eine erhöhte Menge an Wirkstoff mit abgegeben wird, sobald alle Oberflächenbereiche der Matrix mit Körperflüssigkeit durchtränkt sind. Nach längerer Ver­weildauer steht ein stetig sich verminderndes Angebot an Metallionen zur Verfügung, deren Abgabe nunmehr von ihrer Weglänge bei der Wanderung aus dem Inneren der Matrix an deren Oberfläche bestimmt wird.Since the polymer matrix made of silicone polyurethane which forms the device according to the invention contains the entire oligodynamic active ingredient, in addition to the advantage of releasing the metal ions to both outer surfaces of the device body, there is also the advantageous effect that at the beginning of the application, where an increased number of Bacteria, microbes and germs can be present, an increased amount of active ingredient is released as soon as all surface areas of the matrix are saturated with body fluid. After a longer period of time, there is a steadily decreasing supply of metal ions, the release of which is now determined by their path length during the migration from the interior of the matrix to its surface.

Zu diesem Zeitpunkt muß aber auch nur noch gewährleistet sein, daß die - geringe - Anzahl potentiell neu hinzukom­mender Keime sofort abgetötet wird. Die erfindungsgemäße Ausgestaltung des medizinischen Gerätes paßt somit die Ab­gaberate an Metallionen der Menge der momentan zu bekämp­fenden Organismen von selbst an.At this point, however, it only has to be ensured that the - small - number of potentially new germs is immediately killed. The configuration of the medical device according to the invention thus automatically adjusts the rate of release of metal ions to the amount of organisms to be controlled.

Zweckmäßigerweise sollte die Metallionen abgebende Substanz in der Matrix keine Korngrößen größer als 50 µm enthalten, da ein Überschreiten dieser Grenze die mechanische Stabili­tät der Matrix negativ beeinflussen kann.The metal ion-releasing substance should expediently not contain any grain sizes larger than 50 μm, since exceeding this limit can have a negative effect on the mechanical stability of the matrix.

Bei erfindungsgemäß ausgestalteten Harnröhrenkathetern wurde außerdem der vorteilhafte Effekt beobachtet, daß In­krustationen am Katheter, d.h. Überkrustungen mit Minera­lien, in deutlich vermindertem Maße oder gar nicht auftraten.In the case of urethral catheters designed according to the invention, the advantageous effect was also observed that incrustations on the catheter, i.e. Crusting with minerals, to a significantly reduced extent or not at all.

Ein bevorzugtes Verfahren zur Herstellung des erfindungsge­mäßen Gerätes besteht darin, daß man das Polypol, das orga­nische Silikonpolymer sowie das Isocyanat sowie gegebenen­falls die Kettenverlängerer und/oder Vernetzersubstanzen miteinander reagieren läßt und danach in die gewünschte Form bringt.A preferred method for producing the device according to the invention is that the polypol, the organic silicone polymer and the isocyanate and, if appropriate, the chain extenders and / or crosslinking substances are allowed to react with one another and then brought into the desired shape.

Erfindungsgemäß wird dabei die Metallionen abgebende Sub­stanz mit einem Anteil an der Gesamtpolymermasse von 1 bis 15 Gew.-% als Pulver mit einer Korngröße ≦ 50 µm vor der Zugabe des Isocyanats zugemischt und gemeinsam mit dem Po­lyol entwässert. Durch diese Verfahrensabfolge und die Fein­körnigkeit der wirksamen Substanz bei der Zugabe werden fol­gende Vorteile erzielt:According to the invention, the metal ion-donating substance with a proportion of the total polymer mass of 1 to 15% by weight is admixed as a powder with a grain size ≦ 50 μm before the addition of the isocyanate and dewatered together with the polyol. The following advantages are achieved by this sequence of processes and the fine granularity of the active substance when added:

Die getrennten Arbeitsgänge des Trocknens der Metallionen abgebenden Substanz sowie des Polyols und/oder des Polyol­gemisches werden zu einem einzigen Verfahrensschritt zusam­mengefaßt. Die Feinkörnigkeit garantiert die Möglichkeit, die aktive Substanz über den gesamten Querschnitt der Poly­mermatrix besonders gleichmäßig einzubringen. Ein weiteres, besonders bevorzugtes Verfahren besteht darin, daß man an­stelle des Pulvers eine gut wasserlösliche, Metallionen ab­gebende Substanz verwendet und diese als wäßrige Lösung mit einem Feststoff-Anteil wie bei der oben beschriebenen Pul­ver-Zugabe und an gleicher Stelle wie oben zumischt, an­schließend entwässert und dann das Isocyanat zugibt.The separate operations of drying the metal ion-releasing substance and the polyol and / or the polyol mixture are combined into a single process step. The fine grain guarantees the possibility of introducing the active substance particularly evenly over the entire cross section of the polymer matrix. A further, particularly preferred method consists in using a readily water-soluble, metal ion-releasing substance instead of the powder and admixing it as an aqueous solution with a solids content as in the powder addition described above and at the same point as above, and then dewatered and then add the isocyanate.

Diese Verfahrensvariante bietet den Vorteil, die aktive Sub­stanz in kleinstmöglicher Form, nämlich als diskrete Ionen und damit optimal gleichmäßig, in die Matrix einführen zu können.This variant of the method offers the advantage of being able to introduce the active substance into the matrix in the smallest possible form, namely as discrete ions and thus in an optimally uniform manner.

Das anschließende Entwässern führt zu keinen größeren Kri­stall-Agglomeraten, da die polymere Matrix nur die Entste­hung kleiner Kristalle (≦ 50 µm) zuläßt. Zweckmäßig wird da­bei als oligodynamisch aktive Substanz Silbernitrat einge­setzt.The subsequent dewatering does not lead to larger crystal agglomerates, since the polymer matrix only allows the formation of small crystals (≦ 50 µm). Silver nitrate is expediently used as the oligodynamically active substance.

Die erfindungsgemäßen Verfahren besitzen weiterhin folgende Vorteile:The methods according to the invention also have the following advantages:

Es wird eine einstufige Formgebung und bakterizide/mikrobi­zide Ausrüstung des medizinischen Gerätes erzielt. Jegliche Nachbehandlung entfällt, wodurch das Handhaben von Lösungs­mitteln, das Quellen oder Anlösen des Substrates oder Pro­bleme bezüglich der Haftung von Beschichtungen vollständig umgangen werden können.A one-step shaping and bactericidal / microbicidal treatment of the medical device is achieved. Any post-treatment is eliminated, which completely eliminates the handling of solvents, the swelling or dissolving of the substrate or problems with the adhesion of coatings.

Will man einen thermoplastischen Werkstoff erhalten, wird das fertig hergestellte, mit Wirkstoff ausgerüstete Poly­urethan granuliert, getrocknet und anschließend entweder spritzgegossen oder extrudiert. Für die Herstellung von du­roplastischen Geräten, z. B. Sonden, erfolgt die Formgebung sofort nach der Reaktion der Ausgangsstoffe durch Ausgießen in ein Formteil.If you want to obtain a thermoplastic material, the finished polyurethane with active ingredient is granulated, dried and then either injection molded or extruded. For the production of thermoset devices, e.g. B. probes, the shaping takes place immediately after the reaction of the starting materials by pouring into a molded part.

In jedem Falle kann das gewünschte medizinische Gerät in einem kontinuierlich verlaufenden Verfahrensschritt herge­stellt werden.In any case, the desired medical device can be manufactured in a continuous process step.

Anhand des folgenden Beispieles wird in nicht einschränken­der Weise ein Herstellungsverfahren für ein medizinisches Gerät aus einem thermoplastischen Werkstoff detailliert be­schrieben:The following example describes a manufacturing method for a medical device made of a thermoplastic material in a non-restrictive manner:

100 Teile eines OH-terminierten, bifunktionellen Polyesters mit dem Molekulargewicht 2.000 g/mol (Basis: Adipinsäure, Neopentylglykol plus Hexandiol), wie er sich unter der Be­zeichnung Desmophen 2028 der Bayer AG im Handel befindet, werden mit 20 Teilen eines linearen, entständige Hydroxyl­gruppen aufweisenden Polydimethylsiloxans (Molekulargewicht 2.000 g/mol) und 6 Teilen pulverisierten Silbernitrats (Korn­größe ≦ 50 µm) gemischt und eine Stunde bei 120° C im Vaku­um entwässert. Danach wird das entstandene Präpolymer mit 40 Teilen Diphenylmethan-4,4′-diisocyanat gemischt und nach dem Ausreagieren mit 9 Teilen Butandiol die Polymerkette verlängert.100 parts of an OH-terminated, bifunctional polyester with a molecular weight of 2,000 g / mol (based on adipic acid, neopentyl glycol plus hexanediol), as it is commercially available under the name Desmophen 2028 from Bayer AG, are mixed with 20 parts of a linear, hydroxyl group polydimethylsiloxane (molecular weight 2,000 g / mol) and 6 parts of powdered silver nitrate (grain size ≦ 50 microns) mixed and dehydrated at 120 ° C in a vacuum. Then the resulting prepolymer is mixed with 40 parts of diphenylmethane-4,4'-diisocyanate and after the reaction with 9 parts of butanediol, the polymer chain is extended.

Das fertige Produkt wird auf der Heizplatte aushärten ge­lassen, anschließend granuliert und zwei Stunden bei 110°C in einem Warmluftofen getrocknet. Zum Schluß wird das Gra­nulat auf einer Spritzgießmaschine in die Form eines Harn­röhrenkatheters gebracht.The finished product is allowed to harden on the hot plate, then granulated and dried in a warm air oven at 110 ° C. for two hours. Finally, the granules are shaped into an urethral catheter on an injection molding machine.

Der so gefertigte Katheter besizt die folgenden Material­eigenschaften:

Zugfestigkeit (DIN 53 504) : 20 MPa
Bruchdehnung (DIN 53 504) : 500%
Härte (DIN 53 305) : 70 shore A

Diese Materialdaten zeigen die mechanische Eignung des ther­moplastischen Werkstoffes für die Herstellung von Kathetern und Implantaten.The catheter manufactured in this way has the following material properties:

Tensile strength (DIN 53 504): 20 MPa
Elongation at break (DIN 53 504): 500%
Hardness (DIN 53 305): 70 shore A

These material data show the mechanical suitability of the thermoplastic material for the production of catheters and implants.

Die folgende Tabelle zeigt in qualitativer und quantitati­ver Darstellung die mikrobizide Wirkung sowie die Abgabefä­higkeit an oligodynamisch wirkenden Silberionen für eine Polyurethanmatrix gemäß dem Stand der Technik im Vergleich mit einer Silikonpolyurethan-Matrix gemäß der vorliegenden Erfindung:

Figure imgb0001
The following table shows in a qualitative and quantitative representation the microbicidal action and the ability to deliver oligodynamically acting silver ions for a polyurethane matrix according to the prior art in comparison with a silicone-polyurethane matrix according to the present invention:
Figure imgb0001

Claims (3)

1. In das Körpergewebe einzuführendes, bei Kontakt mit Kör­perflüssigkeit bakterizide bzw. mikrobizide Metallionen abgebendes, gewebeverträgliches medizinisches Gerät, be­stehend aus einem Polyurethanwerkstoff und der die Me­tallionen abgebenden Substanz, dadurch gekennzeichnet, daß der Werkstoff ein an sich bekanntes Polyurethan-Ela­stomer ist, in dessen Hauptkette zu weniger als 50 Gew.-% ein organisches Silikonpolymeres mit einem Molekularge­wicht von 500 bis 10.000, gegebenenfalls weichmachende Polyether- oder Polyester-Segmente und ferner, je nach den gewünschten Materialeigenschaften, Kettenverlänge­rer als thermoplastische bzw. Kettenverlängerer und/oder Vernetzungsmittel als duroplastische Eigenschaften ver­leihende Zusätze vorhanden sind, und daß dieses Elasto­mer über seinen gesamten Querschnitt in räumlich gleich­mäßiger Verteilung die Metallionen abgebende Substanz in Mengen von 1 bis zu 15 Gew.-%, bezogen auf die Ge­samtmasse des Elastomeren, eingelagert enthält.1. To be introduced into the body tissue, when in contact with body fluid bactericidal or microbicidal metal ions, tissue-compatible medical device consisting of a polyurethane material and the metal ion-releasing substance, characterized in that the material is a known polyurethane elastomer, in the Main chain to less than 50% by weight of an organic silicone polymer with a molecular weight of 500 to 10,000, optionally plasticizing polyether or polyester segments and, depending on the desired material properties, chain extenders as thermoplastic or chain extenders and / or crosslinking agents as thermosetting properties conferring additives are present, and that this elastomer contains the metal ion-releasing substance in amounts of 1 to 15% by weight, based on the total mass of the elastomer, over its entire cross-section in a spatially uniform distribution. 2. Verfahren zur Herstellung eines medizinischen Gerätes nach Anspruch 1, wobei man das Polyol, das organische Silikonpolymer sowie das Isocyanat sowie gegebenenfalls die Kettenverlängerer und/oder Vernetzersubstanzen mit­einander reagieren läßt und danach in die gewünschte Form bringt, dadurch gekennzeichnet, daß man die Metall­ionen abgebende Substanz mit einem Anteil an der Gesamt­polymermasse von 1 bis 15 Gew.-% als Pulver mit einer Korngröße ≦ 50 µm vor der Zugabe des Isocyanats zumischt und gemeinsam mit dem Polyol entwässert.2. A process for producing a medical device according to claim 1, wherein the polyol, the organic silicone polymer and the isocyanate and optionally the chain extenders and / or crosslinking agents are allowed to react with one another and then brought into the desired shape, characterized in that the metal ions are released Substance with a proportion of the total polymer mass of 1 to 15 wt .-% as a powder with a grain size ≦ 50 microns before the addition of the isocyanate and dewatered together with the polyol. 3. Verfahren zur Herstellung eines medizinischen Gerätes nach Anspruch 1, wobei man das Polyol, das organische Silikonpolymer sowie das Isocyanat sowie gegebenenfalls die Kettenverlängerer und/oder Vernetzersubstanzen mit­einander reagieren läßt und danach in die gewünschte Form bringt, dadurch gekennzeichnet, daß man eine gut wasserlösliche, Metallionen abgebende Substanz verwen­det und diese als wäßrige Lösung mit einem Feststoff-­Anteil an der Gesamtpolymermasse von 1 bis 15 Gew.-% vor der Zugabe des Isocyanats zumischt und gemeinsam mit dem Polyol entwässert.3. A process for producing a medical device according to claim 1, wherein the polyol, the organic silicone polymer and the isocyanate and optionally the chain extenders and / or crosslinking substances are allowed to react with one another and then brought into the desired shape, characterized in that a readily water-soluble Metal ion-releasing substance used and mixed as an aqueous solution with a solids content of the total polymer mass of 1 to 15 wt .-% before the addition of the isocyanate and dewatered together with the polyol.
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WO2004017738A1 (en) * 2002-08-26 2004-03-04 C.R. Bard, Inc. Antimicrobial compositions containing colloids of oligodynamic metals

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FI91827C (en) 1994-08-25
DE3871016D1 (en) 1992-06-17
ATE75953T1 (en) 1992-05-15
ES2031172T3 (en) 1992-12-01
JPH0553142B2 (en) 1993-08-09
DK170231B1 (en) 1995-07-10
EP0302186A3 (en) 1990-08-22
PT88189B (en) 1993-09-30
PT88189A (en) 1989-06-30
FI882682A0 (en) 1988-06-07
GR3005190T3 (en) 1993-05-24
NO882393D0 (en) 1988-05-31
NO174573C (en) 1994-06-01
FI91827B (en) 1994-05-13
DE3725728A1 (en) 1989-02-16
DK309688A (en) 1989-02-05
NO882393L (en) 1989-02-06
US4973320A (en) 1990-11-27
JPH01230368A (en) 1989-09-13
EP0302186B1 (en) 1992-05-13
DE3725728C2 (en) 1989-11-16
FI882682A (en) 1989-02-05
NO174573B (en) 1994-02-21
DK309688D0 (en) 1988-06-07

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